Safety of immune checkpoint modulators beyond PD-1/PD-L1 and CTLA-4 in solid tumors: A meta-analysis

BACKGROUND: : Novel agents targeting immune checkpoints are under development to overcome resistance to PD-1/PD-L1 and CTLA-4 blockade. Incidences of immune-related adverse events (irAEs) and toxicity profiles of novel agents remain unelucidated. METHODS: : We searched PubMed/MEDLINE, EMBASE, and Web of Science for clinical trials evaluating agents targeting co-inhibitory (B7-H3, CD47, TIGIT, LAG-3, and TIM-3) or co-stimulatory checkpoints (OX40, 4-1BB, CD27, ICOS, GITR, CD70, and CD40) in solid tumors. Incidences of any-grade and grade 3 to 5 (G3-5) treatment-related AEs (trAEs) and irAEs were extracted from phase 2 and 3 trials, and phase 1/2 trials with safety information reported at the recommended phase 2 dose. Odds ratios (ORs) from two-arm studies evaluating the addition of LAG-3 or TIGIT blockade to control-arm therapy were pooled, and AE incidences across immunotherapy subtypes were reported using a random-effects meta-analysis. RESULTS: : A systematic review identified 27 clinical trials comprising 3,946 patients. The addition of LAG-3 blockade increased G3-5 trAEs (OR 1.79, 95% confidence interval [CI]: 1.26-2.54, p = 0.001), adrenal insufficiency (G3-5: OR 8.43, 95%CI: 1.04 to 68.37, p = 0.046; any-grade: OR 4.81, 95%CI: 1.81-12.78, p = 0.002) and any-grade arthralgia (OR 2.07, 95%CI: 1.29-3.30, p = 0.002). Adding TIGIT blockade increased any-grade rash (OR 2.32, 95%CI: 1.01 to 5.34, p = 0.048). Meta-analyses revealed varying irAE patterns: G5 trAEs (0.9-2.9%), G3-5 pneumonitis (0.5-5.5%, highest in TIM-3), G3-5 colitis (0.2 to 5.4%, highest in LAG-3), G3-5 hepatitis (1.5-5.5%, highest in TIM-3), G3-5 adrenal insufficiency (1.7 to 8.4%, highest in TIGIT). CONCLUSIONS: : This study highlights the distinct toxicity profiles of novel immunotherapy agents, providing essential safety data to support clinicians as these therapies approach approval.